A human body has a function of removing external substances which have invaded or contacted the body. This function is called the immune system, which is extremely important as a defense system of the human body. The immune system is regulated by the immune regulation system so that it does not respond to the human body's own tissues.
However, if the mechanism of the immune regulation system is destroyed, an excessive response disadvantageous to the human body's own self may occur. The response has adverse effects on the human body such as allergy and sensitivity.
A foreign substance which causes allergy is called an allergen, and various substances such as ticks, pollen, dust, food, and drugs can become an allergen. The expression of allergy differs in each individual, and depending on the affected area, various symptoms occur, such as hives or atopic dermatitis in the case of skin, allergic rhinitis in the case of nose, and bronchitis in the case of bronchus.
In general, allergic symptoms are said to occur in response to the stimulation of an allergen which causes mast cell degranulation, so that a chemical mediator (chemical messenger) is released to trigger an inflammatory response leading to the onset of the symptom. First, a release of histamine, leukotriene, and the like triggers an immediate response such as vasodilation, vascular hyperpermeability, mucus secretion, nerve stimulation, and respiratory stenosis, and then follows a release of cytokine and the like a few hours later, which lets an inflammatory cell roll on and adhere to a vascular wall, migrate to the tissue and be activated, resulting in a delayed response. That is, allergy symptoms are triggered by mast cell degranulation.
The drugs which alleviate and treat such allergy symptoms are antiallergic agents. Antiallergic agents work to suppress inflammatory responses by controlling a release or an action of a chemical mediator such as histamine.
Examples of the well known antiallergic agents may include histamine antagonists, mast cell degranulation inhibitors, chemical synthesis inhibitors, and antibody production inhibitors. In these antiallergic agents, mast cell degranulation inhibitors are drugs capable of suppressing, as described above, allergic episodes at the stage of degranulation.
Conventionally, external steroid preparations have usually been used for allergic skin diseases such as atopic dermatitis, and great therapeutic effects have been achieved. However, the use of steroid requires a greatest care, and depending on the conditions, for example, the type of steroid, dosage, the number of doses, and whether it is chronically administered or not, and the like, side effects may occur, such as skin atrophy, dry skin, infection induction resulting from a decrease in immunity, photosensitivity, and dyschromia. In addition, a special care must be taken when steroid is given to infants or elderly persons who have delicate skin.
Therefore, mast cell degranulation inhibitors such as tranilast and sodium cromoglycate are expected to be drugs which replace the above-described steroid, and have been used for skin diseases such as atopic dermatitis. In such allergic skin diseases, since degranulation from mast cells occurs in a diseased area of the skin, a topical administration directly to the diseased area of the skin may be preferred.
Further, drugs such as tranilast have been observed to cause serious side effects such as hepatic dysfunction and renal dysfunction by oral administration (Pharmaceutical Products Interview Form (Revised in April, 2004); Sekiseed Capsules, Sekiseed Dry Syrup). Therefore, in order also to alleviate such side effects, the development of external preparations has increasingly been desired.
However, mast cell degranulation inhibitors are at present commercially available only in such forms as a preparation for oral or transmucosal administration or as an ophthalmic solution (e.g., Pharmaceutical Products Interview Form (Revised in April, 2004); Sekiseed Capsules, Sekiseed Dry Syrup). It is because many of the mast cell degranulation inhibitors have low transdermal penetration.
Also, in the mast cell degranulation inhibitors, there are drugs having extremely poor photostability. Accordingly, they are not suitable for external preparations which are directly affected by light. For example, tranilast exemplified as above is considerably unstable to light (Pharmaceutical Products Interview Form (Revised in April, 2004); Sekiseed Capsules, Sekiseed Dry Syrup). Therefore, even if tranilast is administered as an external preparation on the diseased area of skin, a considerable decrease in the amount of tranilast contained therein by light exposure may occur, and the decomposed matter of tranilast and the like may be absorbed in the body, so that there is a risk of causing unexpected adverse effects within a living body such as allergic reaction.
In order to ensure the stability of tranilast to light exposure, for example, methods in which tranilast is used as the dosage form of capsule or in which tranilast is stored with protection from light have been studied (Pharmaceutical Products Interview Form (Revised in April, 2004); Sekiseed Capsules, Sekiseed Dry Syrup). However, in these methods, although the stability of the preparation itself when stored is considered, there is no disclosure about the stability of the preparation after administration. In the case where tranilast takes a dosage form in which it is not exposed to light after administration, for example, such as an internal drug or an ophthalmic solution, it is sufficient to ensure the stability of the preparation as described above. However, in the case where tranilast is administered on the diseased area of skin as an external preparation such as an ointment, although it may be an idea to cover the diseased area to protect from light after the external preparation is applied, such protection from light may become extremely difficult depending on the diseased area of skin.
Accordingly, with respect to tranilast, it is difficult to formulate this drug as an external preparation because of its low transdermal penetration, and even if an external preparation of tranilast is successfully formulated, an improvement of photostability will be required.
Incidentally, in Japanese Patent Laid-open Publication No. 2001-513483 (CLAIMS, [0038]) , the use of a long-acting topical anesthetic in order to suppress cerebral neurovascular disorders is described, and specific examples of the topical anesthetic may include bupivacaine. Also, in Japanese Patent Laid-open Publication No. 2001-513483, there is a description that a mast cell degranulation inhibitor may be added to the above-described pharmaceutical composition. However, the technique according to Japanese Patent Laid-open Publication No. 2001-513483 has an object of alleviating the headache, and it is a technique in which the medical composition is administered transnasally, and it is not intended for skin diseases or transdermal administration. Furthermore, a mast cell degranulation inhibitor is only an example of substances which is supplementarily added in order to suppress histamine headache in various types of headaches, and there is no description of a specific preparation containing both a mast cell degranulation inhibitor and a topical anesthetic.
Also, there is a disclosure of a technique in which propolis and a balsaminaceous plant, both of which are said to have mast cell degranulation inhibition action, are used in combination as an external preparation (Japanese Patent Laid-open Publication No. 11-322620). In these ingredients, propolis is considered to also have topical anesthetic action. However, they only enhance antiallergic action by combining mast cell degranulation inhibition action of the two.
Incidentally, an NSAID (i.e., nonsteroidal anti-inflammatory drug) is used as an external preparation for skin diseases as a substitute for steroid. Techniques of producing a preparation of the NSAID by combining an NASID with a topical anesthetic are disclosed, for example, in following literatures: Japanese Patent Laid-open Publication No. 2003-252793 discloses a technique of enhancing anti-inflammatory and analgesic effects and Japanese Patent Laid-open Publication No. 2002-128699 discloses a technique of increasing transdermal penetration, while EP 1 405 646 A2 discloses a technique of preparing a salt of an NSAID and a topical anesthetic.
However, the above literatures are related to the technique of combining an NSAID with a topical anesthetic, and neither tranilast nor degranulation inhibitors are disclosed.